U.S. patent application number 12/599196 was filed with the patent office on 2010-06-10 for novel benzamidine derivatives useful as potassium channel modulators.
This patent application is currently assigned to Neuro Search A/S. Invention is credited to Palle Christophersen, Joachim Demnitz, Morten Grunnet, David Spencer Jones, Lars Siim Madsen, Antonio Nardi, Elsebet Ostergaard Nielsen, Dorte Strob.ae butted.k.
Application Number | 20100144809 12/599196 |
Document ID | / |
Family ID | 39712013 |
Filed Date | 2010-06-10 |
United States Patent
Application |
20100144809 |
Kind Code |
A1 |
Nardi; Antonio ; et
al. |
June 10, 2010 |
NOVEL BENZAMIDINE DERIVATIVES USEFUL AS POTASSIUM CHANNEL
MODULATORS
Abstract
This invention relates to novel benzamidine derivatives of
formula (I) that are found to be potent modulators of potassium
channels and, as such, are valuable candidates for the treatment of
diseases or disorders as diverse as those which are responsive to
the modulation of potassium channels. A stereoisomer or a mixture
of its stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof, wherein B may be
absent (i.e. no heterocyclic ring is formed); and when absent, the
nitrogen next to B holds a hydrogen (i.e. "NH"), and A represents
NH.sub.2 or OH; or B may be present (i.e. forms part of a
heterocyclic ring); and when present, B represents C.dbd.O or
C.dbd.S; and A represents NH or O; and wherein the rest of
variables are as specified in claim 1. ##STR00001##
Inventors: |
Nardi; Antonio; (Ballerup,
DK) ; Demnitz; Joachim; (Kobenhavn N, DK) ;
Grunnet; Morten; (Kobenhavn O, DK) ; Christophersen;
Palle; (Ballerup, DK) ; Jones; David Spencer;
(Smorum, DK) ; Nielsen; Elsebet Ostergaard;
(Kobenhavn K, DK) ; Strob.ae butted.k; Dorte;
(Farum, DK) ; Madsen; Lars Siim; (Soro,
DK) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
Neuro Search A/S
Ballerup
DK
|
Family ID: |
39712013 |
Appl. No.: |
12/599196 |
Filed: |
May 7, 2008 |
PCT Filed: |
May 7, 2008 |
PCT NO: |
PCT/EP2008/055628 |
371 Date: |
January 5, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60916881 |
May 9, 2007 |
|
|
|
Current U.S.
Class: |
514/381 ;
548/252; 548/253; 548/254 |
Current CPC
Class: |
A61P 17/14 20180101;
A61P 25/04 20180101; C07D 403/10 20130101; A61P 1/00 20180101; A61P
11/00 20180101; A61P 15/10 20180101; A61P 21/02 20180101; A61P
25/16 20180101; A61P 9/10 20180101; A61P 11/08 20180101; A61P 13/10
20180101; A61P 25/08 20180101; A61P 25/24 20180101; A61P 9/12
20180101; A61P 27/00 20180101; A61P 35/00 20180101; A61P 13/02
20180101; A61P 13/12 20180101; A61P 25/22 20180101; C07D 257/04
20130101; A61P 15/06 20180101; A61P 9/04 20180101; A61P 13/00
20180101; A61P 25/28 20180101; A61P 15/00 20180101; A61P 43/00
20180101; A61P 1/12 20180101; A61P 3/10 20180101; A61P 25/00
20180101; A61P 25/18 20180101 |
Class at
Publication: |
514/381 ;
548/254; 548/253; 548/252 |
International
Class: |
A61K 31/41 20060101
A61K031/41; C07D 257/04 20060101 C07D257/04; A61P 11/00 20060101
A61P011/00; A61P 25/08 20060101 A61P025/08; A61P 25/00 20060101
A61P025/00; A61P 13/10 20060101 A61P013/10; A61P 15/10 20060101
A61P015/10; A61P 15/00 20060101 A61P015/00; A61P 13/00 20060101
A61P013/00; A61P 25/18 20060101 A61P025/18; A61P 25/16 20060101
A61P025/16; A61P 25/24 20060101 A61P025/24; A61P 27/00 20060101
A61P027/00; A61P 17/14 20060101 A61P017/14 |
Foreign Application Data
Date |
Code |
Application Number |
May 8, 2007 |
DK |
PA 2007 00689 |
Claims
1-11. (canceled)
12. A benzamidine derivative of Formula I ##STR00009## a
stereoisomer or a mixture of its stereoisomers, or an N-oxide
thereof, or a pharmaceutically-acceptable addition salt thereof,
wherein B may be absent (i.e. no heterocyclic ring is formed); and
when absent, the nitrogen next to B holds a hydrogen (i.e. "NH"),
and A represents NH.sub.2 or OH; or B may be present (i.e. forms
part of a heterocyclic ring); and when present, B represents
C.dbd.O or C.dbd.S; and A represents NH or O; R.sup.1 represents a
tetrazolyl group; R.sup.2 and R.sup.3, independently of each other,
represent hydrogen, halo, cyano, nitro, hydroxy or phenyl, which
phenyl may optionally be substituted one or more times with halo,
trifluoromethyl and/or hydroxy; and R.sup.4 and R.sup.5,
independently of each other, represent halo, trifluoromethyl,
hydroxy and/or phenyl.
13. The benzamidine derivative of claim 12, a stereoisomer or a
mixture of its stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof, wherein B is be
absent (i.e. no heterocyclic ring is formed); and the nitrogen next
to B holds a hydrogen (i.e. "NH"); and A represents NH, or OH.
14. The benzamidine derivative of claim 12, a stereoisomer or a
mixture of its stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof, wherein B is
present (i.e. forms part of a heterocyclic ring) and represents
C.dbd.O or C.dbd.S; and A represents NH or O.
15. The benzamidine derivative of claim 12, a stereoisomer or a
mixture of its stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof, wherein R.sup.1
represents a tetrazolyl group.
16. The benzamidine derivative of claim 12, a stereoisomer or a
mixture of its stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof, wherein R.sup.2
and R.sup.3, independently of each other, represent hydrogen, halo,
cyano, nitro, hydroxy or phenyl, which phenyl may optionally be
substituted one or more times with halo, trifluoromethyl and/or
hydroxy.
17. The benzamidine derivative of claim 12, a stereoisomer or a
mixture of its stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof, wherein R.sup.4
and R.sup.5, independently of each other, represent halo,
trifluoromethyl, hydroxy and/or phenyl.
18. The benzamidine derivative of claim 12, which is
N-Amino-N'-[3-(1H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl]-3,5-bi-
s-trifluoromethyl-benzamidine;
5-(3,5-Bis-trifluoromethyl-phenyl)-4-[3-(2H-tetrazol-5-yl)-4'-trifluorome-
thyl-biphenyl-4-yl]-2,4-dihydro-[1,2,4]triazol-3-one; or
N-Hydroxy-N'-[3-(1H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl]-3,5--
bis-trifluoromethyl-benzamidine; a stereoisomer or a mixture of its
stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof.
19. A pharmaceutical composition comprising a therapeutically
effective amount of the benzamidine derivative of claim 12, a
stereoisomer or a mixture of its stereoisomers, or an N-oxide
thereof, or a pharmaceutically-acceptable addition salt thereof,
together with one or more adjuvants, excipients, carriers and/or
diluents.
20. A method of treatment, prevention or alleviation of a disease
or a disorder or a condition of a living animal body, including a
human, which disorder, disease or condition is responsive to
modulation of potassium channels, which method comprises the step
of administering to such a living animal body in need thereof, a
therapeutically effective amount of the benzamidine derivative
according to claim 12, a stereoisomer or a mixture of its
stereoisomers, or an N-oxide thereof, or a
pharmaceutically-acceptable addition salt thereof
21. The method according to claim 20, wherein the disease, disorder
or condition is a respiratory disease, epilepsy, convulsions,
seizures, absence seizures, vascular spasms, coronary artery
spasms, motor neuron diseases, myokymia, renal disorders,
polycystic kidney disease, bladder hyperexcitability, bladder
spasms, urinogenital disorders, urinary incontinence, bladder
outflow obstruction, erectile dysfunction, gastrointestinal
dysfunction, gastrointestinal hypomotility disorders,
gastrointestinal motility insufficiency, postoperative ileus,
constipation, gastroesophageal reflux disorder, secretory
diarrhoea, an obstructive or inflammatory airway disease,
ischaemia, cerebral ischaemia, ischaemic heart disease, angina
pectoris, coronary heart disease, ataxia, traumatic brain injury,
stroke, Parkinson's disease, bipolar disorder, psychosis,
schizophrenia, autism, anxiety, mood disorders, depression, manic
depression, psychotic disorders, dementia, learning deficiencies,
age related memory loss, memory and attention deficits, Alzheimer's
disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea,
narcolepsy, sleeping disorders, sleep apnea, Reynaud's disease,
intermittent claudication, Sjogren's syndrome, xerostomia,
cardiovascular disorders, hypertension, myotonic dystrophy,
myotonic muscle dystrophia, spasticity, xerostomi, diabetes Type
II, hyperinsulinemia, premature labour, cancer, brain tumors,
inflammatory bowel disease, irritable bowel syndrome, colitis,
colitis Crohn, immune suppression, hearing loss, migraine, pain,
neuropathic pain, inflammatory pain, trigeminal neuralgia, vision
loss, rhinorrhoea, ocular hypertension (glaucoma) or baldness.
Description
TECHNICAL FIELD
[0001] This invention relates to novel benzamidine derivatives that
are found to be potent modulators of potassium channels and, as
such, are valuable candidates for the treatment of diseases or
disorders as diverse as those which are responsive to the
modulation of potassium channels.
BACKGROUND ART
[0002] Ion channels are cellular proteins that regulate the flow of
ions through cellular membranes of all cells and are classified by
their selective permeability to the different of ions (potassium,
chloride, sodium etc.). Potassium channels, which represent the
largest and most diverse sub-group of ion channels, selectively
pass potassium ions and, doing so, they principally regulate the
resting membrane potential of the cell and/or modulate their level
of excitation.
[0003] Dysfunction of potassium channels, as well as other ion
channels, generates loss of cellular control resulting in altered
physiological functioning and disease conditions. Ion channel
blockers and openers, by their ability to modulate ion channel
function and/or regain ion channel activity in acquired or
inherited channelopathies, are being used in the pharmacological
treatment of a wide range of pathological diseases and have the
potential to address an even wider variety of therapeutic
indications. For instance, the primary indications for potassium
channel openers encompass conditions as diverse as diabetes,
arterial hypertension, cardiovascular diseases, urinary
incontinence, atrial fibrillation, epilepsy, pain, and cancer.
[0004] Among the large number of potassium channel types, the
large-conductance calcium-activated potassium channel subtype is an
obvious site for pharmacological intervention and for the
development of new potassium channel modulators. Their
physiological role has been especially studied in the nervous
system, where they are key regulators of neuronal excitability and
of neurotransmitter release, and in smooth muscle, where they are
crucial in modulating the tone of vascular, broncho-tracheal,
urethral, uterine or gastro-intestinal musculature.
[0005] Given these implications, small agents with BK-opening
properties could have a potentially powerful influence in the
modulation and control of numerous consequences of muscular and
neuronal hyperexcitability, such as asthma, urinary incontinence
and bladder spasm, gastroenteric hypermotility, psychoses,
post-stroke neuroprotection, convulsions, anxiety and pain. As far
as the cardiovascular system is concerned, the physiological
function of these ion channels represents a fundamental steady
state mechanism, modulating vessel depolarisation, vasoconstriction
and increases of intravascular pressure, and the development of
selective activators of BK channels is seen as a potential
pharmacotherapy of vascular diseases, including hypertension,
erectile dysfunction, coronary diseases and vascular complications
associated with diabetes or hypercholesterolemia.
[0006] WO 2006/055760 and WO 2007/139967 describe triazoles
derivatives useful as HSP90 inhibitors for the treatment of e.g.
cancer. However, the benzamidine derivatives of the present
invention have not been described and their activity as potassium
channel modulators certainly no suggested.
SUMMARY OF THE INVENTION
[0007] It is an object of the invention to provide novel
benzamidine derivatives useful as potassium channel modulators. The
benzamidine derivatives of the invention may be characterised by
Formula I
##STR00002##
[0008] a stereoisomer or a mixture of its stereoisomers, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein
[0009] B may be absent (i.e. no heterocyclic ring is formed); and
when absent, the nitrogen next to B holds a hydrogen (i.e. "NH");
and A represents NH.sub.2 or OH; or
[0010] B may be present (i.e. forms part of a heterocyclic ring);
and when present, B represents C.dbd.O or C.dbd.S; and A represents
NH or O;
[0011] R.sup.1 represents a tetrazolyl group;
[0012] R.sup.2 and R.sup.3, independently of each other, represent
hydrogen, halo, cyano, nitro, hydroxy or phenyl, which phenyl may
optionally be substituted one or more times with halo,
trifluoromethyl and/or hydroxy; and
[0013] R.sup.4 and R.sup.5, independently of each other, represent
halo, trifluoromethyl, hydroxy and/or phenyl.
[0014] In another aspect the invention provides pharmaceutical
compositions comprising a therapeutically effective amount of a
benzamidine derivative of the invention.
[0015] In a third aspect the invention relates to the use of the
benzamidine derivatives of the invention for the manufacture of
pharmaceutical compositions.
[0016] In a further aspect the invention provides a method of
treatment, prevention or alleviation of a disease or a disorder or
a condition of a living animal body, including a human, which
disorder, disease or condition is responsive to modulation of
potassium channels, which method comprises the step of
administering to such a living animal body in need thereof, a
therapeutically effective amount of the benzamidine derivative of
the invention.
[0017] Other objects of the invention will be apparent to the
person skilled in the art from the following detailed description
and examples.
DETAILED DISCLOSURE OF THE INVENTION
[0018] In its first aspect the invention provides novel benzamidine
derivatives of Formula I
##STR00003##
[0019] a stereoisomer or a mixture of its stereoisomers, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein
[0020] B may be absent (i.e. no heterocyclic ring is formed); and
when absent, the nitrogen next to B holds a hydrogen (i.e. "NH");
and A represents NH.sub.2 or OH; or
[0021] B may be present (i.e. forms part of a heterocyclic ring);
and when present, B represents C.dbd.O or C.dbd.S; and A represents
NH or O;
[0022] R.sup.1 represents a tetrazolyl group;
[0023] R.sup.2 and R.sup.3, independently of each other, represent
hydrogen, halo, cyano, nitro, hydroxy or phenyl, which phenyl may
optionally be substituted one or more times with halo,
trifluoromethyl and/or hydroxy; and
[0024] R.sup.4 and R.sup.5, independently of each other, represent
halo, trifluoromethyl, hydroxy and/or phenyl.
[0025] In a preferred embodiment the benzamidine derivatives of the
invention is a compound of Formula I, a stereoisomer or a mixture
of its stereoisomers, or a pharmaceutically-acceptable addition
salt thereof, wherein
[0026] A represents a nitrogen (N) or an oxygen (O) atom;
[0027] B is absent (i.e. no heterocyclic ring is formed) or is
present (i.e. forms part of a heterocyclic ring); and when present,
B represents C.dbd.O or C.dbd.S;
[0028] R.sup.1 represents a tetrazolyl group;
[0029] R.sup.2 and R.sup.3, independently of each other, represent
hydrogen, halo, cyano, nitro, hydroxy or phenyl, which phenyl may
optionally be substituted one or more times with halo,
trifluoromethyl and/or hydroxy; and
[0030] R.sup.4 and R.sup.5, independently of each other, represent
halo, trifluoromethyl, hydroxy and/or phenyl.
[0031] In another preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula Ia
##STR00004##
[0032] a stereoisomer or a mixture of its stereoisomers, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein
[0033] B may be absent (i.e. no heterocyclic ring is formed); and
when absent, the nitrogen next to B holds a hydrogen (i.e. "NH");
and A represents NH.sub.2 or OH; or
[0034] B may be present (i.e. forms part of a heterocyclic ring);
and when present, B represents C.dbd.O or C.dbd.S; and A represents
NH or O; and R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as defined
above, (i.e. R.sup.3 represent hydrogen).
[0035] In a third preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula Ia a stereoisomer or a
mixture of its stereoisomers, or a pharmaceutically-acceptable
addition salt thereof, wherein A, B, R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are as defined above, (i.e. R.sup.3 represent
hydrogen).
[0036] In a fourth preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula Ib
##STR00005##
[0037] a stereoisomer or a mixture of its stereoisomers, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein
[0038] B may be absent (i.e. no heterocyclic ring is formed); and
when absent, the nitrogen next to B holds a hydrogen (i.e. "NH");
and A represents NH.sub.2 or OH; or
[0039] B may be present (i.e. forms part of a heterocyclic ring);
and when present, B represents C.dbd.O or C.dbd.S; and A represents
NH or O; and
[0040] R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as defined above
(i.e. R.sup.3 represent hydrogen).
[0041] In a fifth preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula Iba stereoisomer or a
mixture of its stereoisomers, or a pharmaceutically-acceptable
addition salt thereof, wherein A, B, R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are as defined above (i.e. R.sup.3 represent hydrogen).
[0042] In a sixth preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula Ic
##STR00006##
[0043] a stereoisomer or a mixture of its stereoisomers, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein
[0044] A represents NH2 or OH; and
[0045] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
defined above.
[0046] In a seventh preferred embodiment, the benzamidine
derivative of the invention is a compound of Formula Ica
stereoisomer or a mixture of its stereoisomers, or a
pharmaceutically-acceptable addition salt thereof, wherein A,
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined
above.
[0047] In an eighth preferred embodiment, the benzamidine
derivative of the invention is a compound of Formula I, Ia or Ib,
or an N-oxide thereof, or a pharmaceutically-acceptable addition
salt thereof, wherein
[0048] B is be absent (i.e. no heterocyclic ring is formed); and
the nitrogen next to B holds a hydrogen (i.e. "NH"), and
[0049] A represents NH.sub.2 or OH.
[0050] In a more preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula I, Ia, Ib or Ic, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein A represents a nitrogen (N) or an oxygen (O)
atom.
[0051] In another more preferred embodiment, A represents a
nitrogen (N) atom.
[0052] In a third more preferred embodiment, A represents an oxygen
(O) atom.
[0053] In a fourth more preferred embodiment, A represents
NH.sub.2.
[0054] In a fifth more preferred embodiment, A represents OH.
[0055] In a ninth preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula I, Ia or Ib, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein B is present (i.e. forms part of a heterocyclic
ring) and represents C.dbd.O or C.dbd.S; and A represents NH or
O.
[0056] In a more preferred embodiment, B is represents C.dbd.O; and
A represents NH or O.
[0057] In another more preferred embodiment, B is represents
C.dbd.O; and A represents NH.
[0058] In a third more preferred embodiment, B is represents
C.dbd.O; and A represents O.
[0059] In a fourth more preferred embodiment, B is represents
C.dbd.S; and A represents NH or O.
[0060] In a fifth more preferred embodiment, B is represents
C.dbd.S; and A represents NH.
[0061] In a sixth more preferred embodiment, B is represents
C.dbd.S; and A represents O.
[0062] In a tenth preferred embodiment, the benzamidine derivative
of the invention is a compound of Formula I, Ia or Ib, or an
N-oxide thereof, or a pharmaceutically-acceptable addition salt
thereof, wherein B is absent (i.e. no heterocyclic ring is formed),
or B is present (i.e. forms part of a heterocyclic ring); and when
present, B represents C.dbd.O or C.dbd.S.
[0063] In a more preferred embodiment B is present (i.e. forms part
of a heterocyclic ring); and presents C.dbd.O or C.dbd.S.
[0064] In another more preferred embodiment B is present (i.e.
forms part of a heterocyclic ring); and presents C.dbd.O.
[0065] In a third more preferred embodiment B is present (i.e.
forms part of a heterocyclic ring); and presents C.dbd.S.
[0066] In a fourth more preferred embodiment, the benzamidine
derivative of the invention is a compound of Formula Ic, i.e. B is
absent (and no heterocyclic ring is formed).
[0067] In an eleventh preferred embodiment, the benzamidine
derivative of the invention is a compound of Formula I, Ia, Ib or
Ic, or an N-oxide thereof, or a pharmaceutically-acceptable
addition salt thereof, wherein R.sup.1 represents a tetrazolyl
group.
[0068] In a more preferred embodiment R.sup.1 represents a
1H-tetrazol-5-yl or 2H-tetrazol-5-yl group.
[0069] In another more preferred embodiment R.sup.1 represents a
1H-tetrazol-5-yl group.
[0070] In a third more preferred embodiment R.sup.1 represents a
2H-tetrazol-5-yl group.
[0071] In a twelfth preferred embodiment, the benzamidine
derivative of the invention is a compound of Formula I, Ia, Ib or
Ic, or an N-oxide thereof, or a pharmaceutically-acceptable
addition salt thereof, wherein R.sup.2 and R.sup.3, independently
of each other, represent hydrogen, halo, cyano, nitro, hydroxy or
phenyl, which phenyl may optionally be substituted one or more
times with halo, trifluoromethyl and/or hydroxy.
[0072] In a more preferred embodiment R.sup.2 and R.sup.3,
independently of each other, represent hydrogen or phenyl, which
phenyl may optionally be substituted one or more times with halo,
trifluoromethyl and/or hydroxy.
[0073] In another more preferred embodiment R.sup.2 represents
phenyl, which phenyl may optionally be substituted one or more
times with halo, trifluoromethyl and/or hydroxy; and R.sup.3
represents hydrogen.
[0074] In a third more preferred embodiment R.sup.2 represents
phenyl substituted with halo, trifluoromethyl or hydroxy; and
R.sup.3 represents hydrogen.
[0075] In a fourth more preferred embodiment R.sup.2 represents
phenyl substituted with trifluoromethyl; and R.sup.3 represents
hydrogen.
[0076] In a thirteenth preferred embodiment, the benzamidine
derivative of the invention is a compound of Formula I, Ia, Ib or
Ic, or an N-oxide thereof, or a pharmaceutically-acceptable
addition salt thereof, wherein R.sup.4 and R.sup.5, independently
of each other, represent halo, trifluoromethyl, hydroxy and/or
phenyl.
[0077] In a more preferred embodiment R.sup.4 and R.sup.5,
independently of each other, represent halo, trifluoromethyl and/or
phenyl.
[0078] In another more preferred embodiment R.sup.4 and R.sup.5,
independently of each other, represent halo or trifluoromethyl.
[0079] In a third more preferred embodiment R.sup.4 and R.sup.5
both represent halo, trifluoromethyl or phenyl.
[0080] In a fourth more preferred embodiment R.sup.4 and R.sup.5
both represent halo, trifluoromethyl, hydroxy and/or phenyl.
[0081] In a fifth more preferred embodiment R.sup.4 and R.sup.5
both represent halo or trifluoromethyl.
[0082] In a sixth more preferred embodiment R.sup.4 and R.sup.5
both represent trifluoromethyl.
[0083] In a most preferred embodiment the benzamidine derivative of
the invention is
[0084]
N-Amino-N'-[3-(1H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl]--
3,5-bis-trifluoromethyl-benzamidine;
[0085]
5-(3,5-Bis-trifluoromethyl-phenyl)-4-[3-(2H-tetrazol-5-yl)-4'-trifl-
uoromethyl-biphenyl-4-yl]-2,4-dihydro-[1,2,4]triazol-3-one; or
[0086]
N-Hydroxy-N'-[3-(1H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl-
]-3,5-bis-trifluoromethyl-benzamidine;
[0087] or a pharmaceutically-acceptable addition salt thereof.
[0088] Any combination of two or more of the embodiments described
herein is considered within the scope of the present invention.
Definition of Substituents
[0089] In the context of this invention halo represents fluoro,
chloro, bromo or iodo.
Pharmaceutically Acceptable Salts
[0090] The benzamidine derivatives of the invention may be provided
in any form suitable for the intended administration. Suitable
forms include pharmaceutically (i.e. physiologically) acceptable
salts, and pre- or prodrug forms of the benzamidine derivative of
the invention.
[0091] Examples of pharmaceutically acceptable addition salts
include, without limitation, the non-toxic inorganic and organic
acid addition salts such as the hydrochloride, the hydrobromide,
the nitrate, the perchlorate, the phosphate, the sulphate, the
formate, the acetate, the aconate, the ascorbate, the
benzenesulphonate, the benzoate, the cinnamate, the citrate, the
embonate, the enantate, the fumarate, the glutamate, the glycolate,
the lactate, the maleate, the malonate, the mandelate, the
methanesulphonate, the naphthalene-2-sulphonate derived, the
phthalate, the salicylate, the sorbate, the stearate, the
succinate, the tartrate, the toluene-p-sulphonate, and the like.
Such salts may be formed by procedures well known and described in
the art.
[0092] Examples of pharmaceutically acceptable cationic salts of a
benzamidine derivative of the invention include, without
limitation, the sodium, the potassium, the calcium, the magnesium,
the lithium, and the ammonium salt, and the like, of a benzamidine
derivative of the invention containing an anionic group. Such
cationic salts may be formed by procedures well known and described
in the art.
Steric Isomers
[0093] It will be appreciated by those skilled in the art that the
compounds of the present invention may exist in different
stereoisomeric forms, including enantiomers, diastereomers, as well
as geometric isomers (cis-trans isomers). The invention includes
all such isomers and any mixtures thereof including racemic
mixtures.
[0094] Racemic forms can be resolved into the optical antipodes by
known methods and techniques. One way of resolving racemates into
the optical antipodes is based upon chromatography on an optical
active matrix. Racemic compounds of the present invention can thus
be resolved into their optical antipodes, e.g., by fractional
crystallisation of D- or L-(tartrates, mandelates, or
camphorsulphonate) salts for example.
[0095] Additional methods for the resolving the optical isomers are
known in the art. Such methods include those described by Jaques J,
Collet A, & Wilen S in "Enantiomers, Racemates, and
Resolutions", John Wiley and Sons, New York (1981).
[0096] Optical active compounds can also be prepared from optically
active starting materials or intermediates.
Methods of Preparation
[0097] The compounds according to the invention may be prepared by
conventional methods for chemical synthesis, e.g. those described
in the working examples.
Biological Activity
[0098] The benzamidine derivatives of the invention have been found
to possess potassium channel modulating activity as measured by
standard electrophysiological methods. Due to their activity at the
potassium channels, the benzamidine derivatives of the invention
are considered useful for the treatment of a wide range of diseases
and conditions.
[0099] In a special embodiment, the benzamidine derivatives of the
invention are considered useful for the treatment, prevention or
alleviation of a respiratory disease, epilepsy, convulsions,
seizures, absence seizures, vascular spasms, coronary artery
spasms, motor neuron diseases, myokymia, renal disorders,
polycystic kidney disease, bladder hyperexcitability, bladder
spasms, urinogenital disorders, urinary incontinence, bladder
outflow obstruction, erectile dysfunction, gastrointestinal
dysfunction, gastrointestinal hypomotility disorders,
gastrointestinal motility insufficiency, postoperative ileus,
constipation, gastroesophageal reflux disorder, secretory
diarrhoea, an obstructive or inflammatory airway disease,
ischaemia, cerebral ischaemia, ischaemic heart disease, angina
pectoris, coronary heart disease, ataxia, traumatic brain injury,
stroke, Parkinson's disease, bipolar disorder, psychosis,
schizophrenia, autism, anxiety, mood disorders, depression, manic
depression, psychotic disorders, dementia, learning deficiencies,
age related memory loss, memory and attention deficits, Alzheimer's
disease, amyotrophic lateral sclerosis (ALS), dysmenorrhoea,
narcolepsy, sleeping disorders, sleep apnoea, Reynaud's disease,
intermittent claudication, Sjogren's syndrome, xerostomia,
cardiovascular disorders, hypertension, myotonic dystrophy,
myotonic muscle dystrophia, spasticity, xerostomia, diabetes Type
II, hyperinsulinemia, premature labour, cancer, brain tumours,
inflammatory bowel disease, irritable bowel syndrome, colitis,
colitis Crohn, immune suppression, hearing loss, migraine, pain,
neuropathic pain, inflammatory pain, trigeminal neuralgia, vision
loss, rhinorrhoea, ocular hypertension (glaucoma) or baldness.
[0100] In a more preferred embodiment, the benzamidine derivatives
of the invention are considered useful for the treatment,
prevention or alleviation of a respiratory disease, urinary
incontinence, erectile dysfunction, anxiety, epilepsy, psychosis,
schizophrenia, bipolar disorder, depression, amyotrophic lateral
sclerosis (ALS), Parkinson's disease or pain.
[0101] In another more preferred embodiment, the benzamidine
derivatives of the invention are considered useful for the
treatment, prevention or alleviation of psychosis, schizophrenia,
bipolar disorder, depression, epilepsy, Parkinson's disease or
pain.
[0102] In a third more preferred embodiment, the benzamidine
derivatives of the invention are considered useful for the
treatment, prevention or alleviation of pain, mild or moderate or
severe pain, pain of acute, chronic or recurrent character, pain
caused by migraine, postoperative pain, phantom limb pain,
inflammatory pain, neuropathic pain, chronic headache, central
pain, pain related to diabetic neuropathy, to post therapeutic
neuralgia, or to peripheral nerve injury.
[0103] In a fourth more preferred embodiment, the benzamidine
derivatives of the invention are considered useful for the
treatment, prevention or alleviation of cardiac ischemia, ischemic
heart disease, hypertrophic heart, cardiomyopathy or failing
heart.
[0104] In a fifth more preferred embodiment, the compounds of the
invention are considered useful for the treatment, prevention or
alleviation of a cardiovascular disease. In a more preferred
embodiment the cardiovascular disease is atherosclerosis,
ischemia/reperfusion, hypertension, restenosis, arterial
inflammation, myocardial ischaemia or ischaemic heart disease.
[0105] In an sixth more preferred embodiment, the compounds of the
invention are considered useful for obtaining preconditioning of
the heart. Preconditioning, which includes ischemic preconditioning
and myocardial preconditioning, describes short periods of ischemic
events before initiation of a long lasting ischemia. The compounds
of the invention are believed having an effect similar to
preconditioning obtained by such ischemic events. Preconditioning
protects against later tissue damage resulting from the long
lasting ischemic events.
[0106] In a seventh more preferred embodiment, the benzamidine
derivatives of the invention are considered useful for the
treatment, prevention or alleviation of schizophrenia, depression
or Parkinson's disease.
[0107] In an eight more preferred embodiment, the compounds of the
invention are considered useful for the treatment, prevention or
alleviation of an obstructive or inflammatory airway disease. In a
more preferred embodiment the the obstructive or inflammatory
airway disease is an airway hyperreactivity, a pneumoconiosis such
as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis,
siderosis, silicosis, tabacosis and byssinosis, a chronic
obstructive pulmonary disease (COPD), bronchitis, excerbation of
airways hyperreactivity or cystic fibrosis.
[0108] In its most preferred embodiment the obstructive airway
disease is chronic obstructive pulmonary disease (COPD).
[0109] In a ninth more preferred embodiment, the benzamidine
derivatives of the invention are considered useful for the
treatment, prevention or alleviation of a sexual dysfunction, incl.
male sexual dysfunction and female sexual dysfunction, and incl.
male erectile dysfunction.
[0110] In an even more preferred embodiment the benzamidine
derivative of the invention may be co-administered with a
phosphodiesterase inhibitor, in particular a phosphodiesterase 5
(PDE5) inhibitor, e.g. sildenafil, tadalafil, vardenafil and
dipyridamole, or with an agent that potentiates endothelium-derived
hyperpolarizing factor-mediated responses, in particular calcium
dobesilate or similar 2,5-dihydroxybenzenesulfonate analogs.
[0111] In a most preferred embodiment the benzamidine derivative of
the invention is used in a combination therapy together with
sildenafil, tadalafil, vardenafil or calcium dobesilate.
[0112] It is at present contemplated that a suitable dosage of the
active pharmaceutical ingredient (API) is within the range of from
about 0.1 to about 1000 mg API per day, more preferred of from
about 10 to about 500 mg API per day, most preferred of from about
30 to about 100 mg API per day, dependent, however, upon the exact
mode of administration, the form in which it is administered, the
indication considered, the subject and in particular the body
weight of the subject involved, and further the preference and
experience of the physician or veterinarian in charge.
[0113] Preferred benzamidine derivatives of the invention show a
biological activity in the sub-micromolar and micromolar range,
i.e. of from below 1 to about 100 .mu.M.
Pharmaceutical Compositions
[0114] In another aspect the invention provides novel
pharmaceutical compositions comprising a therapeutically effective
amount of a benzamidine derivative of the invention.
[0115] While a benzamidine derivative of the invention for use in
therapy may be administered in the form of the raw chemical
compound, it is preferred to introduce the active ingredient,
optionally in the form of a physiologically acceptable salt, in a
pharmaceutical composition together with one or more adjuvants,
excipients, carriers, buffers, diluents, and/or other customary
pharmaceutical auxiliaries.
[0116] In a preferred embodiment, the invention provides
pharmaceutical compositions comprising the benzamidine derivative
of the invention together with one or more pharmaceutically
acceptable carriers therefore, and, optionally, other therapeutic
and/or prophylactic ingredients, know and used in the art. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and not harmful to
the recipient thereof.
[0117] The pharmaceutical composition of the invention may be
administered by any convenient route, which suits the desired
therapy. Preferred routes of administration include oral
administration, in particular in tablet, in capsule, in drage, in
powder, or in liquid form, and parenteral administration, in
particular cutaneous, subcutaneous, intramuscular, or intravenous
injection. The pharmaceutical composition of the invention can be
manufactured by any person skilled in the art, by use of standard
methods and conventional techniques, appropriate to the desired
formulation. When desired, compositions adapted to give sustained
release of the active ingredient may be employed.
[0118] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0119] The actual dosage depends on the nature and severity of the
disease being treated, and is within the discretion of the
physician, and may be varied by titration of the dosage to the
particular circumstances of this invention to produce the desired
therapeutic effect. However, it is presently contemplated that
pharmaceutical compositions containing of from about 0.1 to about
500 mg of active ingredient per individual dose, preferably of from
about 1 to about 100 mg, most preferred of from about 1 to about 10
mg, are suitable for therapeutic treatments.
[0120] The active ingredient may be administered in one or several
doses per day. A satisfactory result can, in certain instances, be
obtained at a dosage as low as 0.1 .mu.g/kg i.v. and 1 .mu.g/kg
p.o. The upper limit of the dosage range is presently considered to
be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from
about 0.1 .mu.g/kg to about 10 mg/kg/day i.v., and from about 1
.mu.g/kg to about 100 mg/kg/day p.o.
Pharmaceutical Kits of Parts
[0121] According to the invention there is also provided a kit of
parts comprising at least two separate unit dosage forms (A) and
(B):
[0122] (A) a benzamidine derivative of the invention; and
[0123] (B1) a phosphodiesterase inhibitor; or
[0124] (B2) an agent that potentiates endothelium-derived
hyperpolarizing factor-mediated responses; and optionally
[0125] (C) instructions for the simultaneous, sequential or
separate administration of the benzamidine derivative of A, and the
phosphodiesterase inhibitor of B1, or an agent that potentiates
endothelium-derived hyperpolarizing factor-mediated responses of
B2, to a patient in need thereof.
[0126] In a more preferred embodiment the phosphodiesterase
inhibitor for use according to the invention (B1) is a
phosphodiesterase 5 (PDE5) inhibitor, and in an even more preferred
embodiment the phosphodiesterase inhibitor for use according to the
invention is sildenafil, tadalafil or vardenafil.
[0127] In another more preferred embodiment the agent that
potentiates endothelium-derived hyperpolarizing factor-mediated
responses for use according to the invention (B2) is calcium
dobesilate.
[0128] The benzamidine derivative of the invention and the
phosphodiesterase inhibitor or the agent that potentiates
endothelium-derived hyperpolarizing factor-mediated responses for
use according to the invention may preferably be provided in a form
that is suitable for administration in conjunction with the other.
This is intended to include instances where one or the other of two
formulations may be administered (optionally repeatedly) prior to,
after, and/or at the same time as administration with the other
component.
[0129] Also, the benzamidine derivative of the invention and the
phosphodiesterase inhibitor or the agent that potentiates
endothelium-derived hyperpolarizing factor-mediated responses for
use according to the invention may be administered in a combined
form, or separately or separately and sequentially, wherein the
sequential administration is close in time or remote in time. This
may in particular include that two formulations are administered
(optionally repeatedly) sufficiently closely in time for there to
be a beneficial effect for the patient, that is greater over the
course of the treatment of the relevant condition than if either of
the two formulations are administered (optionally repeatedly)
alone, in the absence of the other formulation, over the same
course of treatment. Determination of whether a combination
provides a greater beneficial effect in respect of, and over the
course of treatment of, a particular condition, will depend upon
the condition to be treated or prevented, but may be achieved
routinely by the person skilled in the art.
[0130] When used in this context, the terms "administered
simultaneously" and "administered at the same time as" include that
individual doses of the positive allosteric nicotine receptor
modulator and the cognitive enhancer are administered within 48
hours, e.g. 24 hours, of each other.
[0131] Bringing the two components into association with each
other, includes that components (A) and (B) may be provided as
separate formulations (i.e. independently of one another), which
are subsequently brought together for use in conjunction with each
other in combination therapy; or packaged and presented together as
separate components of a "combination pack" for use in conjunction
with each other in combination therapy.
Methods of Therapy
[0132] In another aspect the invention provides a method of
treatment, prevention or alleviation of a disease, disorder or
condition of a living animal body, including a human, which
disorder, disease or condition is responsive to activation of a
potassium channel, which method comprises the step of administering
to such a living animal body in need thereof, a therapeutically
effective amount a compound capable of activating the potassium
channel, or a pharmaceutically-acceptable addition salt
thereof.
[0133] The preferred medical indications contemplated according to
the invention are those stated above.
[0134] It is at present contemplated that a suitable dosage of the
active pharmaceutical ingredient (API) is within the range of from
about 0.1 to about 1000 mg API per day, more preferred of from
about 1 to about 500 mg API per day, most preferred of from about 1
to about 100 mg API per day, dependent, however, upon the exact
mode of administration, the form in which it is administered, the
indication considered, the subject and in particular the body
weight of the subject involved, and further the preference and
experience of the physician or veterinarian in charge.
EXAMPLES
[0135] The invention is further illustrated with reference to the
following examples, which are not intended to be in any way
limiting to the scope of the invention as claimed.
Example 1
Preparatory Example
##STR00007##
[0137] The synthetic pathway of the compounds of the invention is
outlined in Scheme 1. It involves coupling between the suitable
benzoylchlorides (Z), commercially available or prepared from the
corresponding commercial benzoic acids by treatment with thionyl
chloride, and a number of 2-(1H-tetrazol-5-yl)-phenylamines (Y), to
afford the correspondent benzamide intermediates X. The aniline
derivatives Y were either synthesised as previously described in
e.g. WO 98/47879 and in Valgeirsson et al. in Journal of Medicinal
Chemistry 2004 47 (27) 6948-6957, or may easily synthesised by
palladium catalyzed Suzuki cross-coupling reaction between
cyano-substituted aryl halides and aryl boronic acids, followed by
the conversion of the resulting cyano derivative to correspondent
tetrazolyl derivative.
[0138] As an example of this latter experimental procedure, the
synthesis of the aniline intermediates C and D are reported in
Scheme 2. As example of synthesis of benzanilides X, the
experimental procedure of the novel intermediate E is reported.
Benzanilides X were then treated with phosphorus pentachloride in
dry toluene (.about.100.degree. C.) to generate the correspondent
iminoyl chlorides (as described by Eloy F et al. in European
Journal of Medicinal Chemistry 1974 9 (6) 602-6), followed by
reaction with a solution of anhydrous hydrazine or hydroxylamine,
to yield the correspondent carbohydradrazonamides or amidoximes
(W). The resulting carbohydradrazonamides or amidoximes finally
undergoes a ring closure with or 1,1'-thiocarbonyldiimidazole, CDI
or triphosgene, to afford derivatives Q described in Scheme 1.
##STR00008##
4-Amino-4'-chloro-biphenyl-3-carbonitrile (Intermediate Compound)
(C)
[0139] To a mixture of the commercial 2-amino-5-bromo-benzonitrile
(5.5 g, 1 eq), 4-chlorobenzeneboronic acid (4.8 g, 1.1 eq),
potassium carbonate (12.7 g, 3.3 eq), dimethoxy ethane (80 ml) and
water (40 ml), bistriphenylphosphine palladium (II) chloride (0.2
g) is added. The resulting mixture is refluxed for 24 hours and
then evaporated to dryness. The residue is purified by flash
chromatography using dichloromethane as eluent (5.32 g, 83%
yield).
4'-Chloro-3-(1H-tetrazol-5-yl)-biphenyl-4-ylamine (Intermediate
Compound) (D)
[0140] A mixture of 4-amino-4'-chloro-biphenyl-3-carbonitrile (5.3
g, 1 eq), sodium azide (2.3 g, 1.5 eq) and trethylamine
hydrochloride (4.9 g, 1.5 eq) is suspended in 40 ml of toluene and
heated (60.degree. C.) overnight. To the reaction mixture, cooled
to room temperature, water and 4M HCl are added, to afford the
title compound as a white precipitate. This was collected by
filtration (4.83 g, 77% yield) and used for the next step without
further purification.
N-[3-(1H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl]-3,5-bis-trifluor-
omethyl-benzamide (Intermediate Compound) (E)
[0141] To a stirred solution of 3-(1
H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-ylamine (0.25 g)
(prepared as described in US 2002037905) in pyridine (4 ml),
commercial 3,5-Bis(trifluoromethyl)benzoylchloride (0.226 g, 1 eq)
is added portion wise and stirring is continued at room temperature
for 12 hours. The resulting reaction mixture is evaporated to
dryness and the solid residue is washed with HCl 1N and water, and
used as such for the next reaction (0.41, yield 91%). LC-ESI-HRMS
of [M-H]- shows 544.0804 Da. Calc. 544.081987 Da, dev. -2.9
ppm.
N-Amino-N'-[3-(1H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl]-3,5-bis-
-trifluoromethyl-benzamidine (1)
[0142] To a stirred solution of intermediate E (0.4 g) in dry
toluene (25 ml) and dry methylene chloride (3 ml), kept under
nitrogen, phosphorus pentachloride (0.76 g, 5 eq) is added and the
mixture refluxed for 20 hours. The reaction mixture is then
evaporated to dryness and the residue is taken up in dry
tetrahydrofuran (40 mL) and cooled to -10.degree. C. To this, a
commercial solution of hydrazine 1M in tetrahydrofuran (7.3 ml, 10
eq) is added and the reaction mixture is allowed to reach room
temperature spontaneously and further stirred for 3 hours at room
temperature. Evaporation to dryness of the new reaction mixture
provided a yellow oil, which crystallized upon treatment with 5 ml
of petroleum ether 40-60 (0.39 g, yield 95%). This crude solid was
easily purified by crystallization from methylene
chloride/petroleum ether (40-60). LC-ESI-HRMS of [M-H]- shows
558.1085 Da. Calc. 558.10887 Da, dev. -0.7 ppm.
5-(3,5-Bis-trifluoromethyl-phenyl)-4-[3-(2H-tetrazol-5-yl)-4'-trifluoromet-
hyl-biphenyl-4-yl]-2,4-dihydro-[1,2,4]triazol-3-one (2)
[0143] To a stirred solution of the compound 1 (0.35 g) in dry
pyridine (3 ml), triphosgene (0.111 g, 0.6 eq) is added and
stirring is continued at room temperature for 20 min. The solution
is heated at 70.degree. C. for 5 hours and the pyridine solution is
purified by prep-LCMS, to provide the title compound as a white
solid (0.04 g, yield 11%). .sup.1H-NMR (DMSO-d.sub.6): 12.43 (1H,
s, NH), 8.41-7.60 (10H, m, aromatics).
N-Hydroxy-N'-[3-(1H-tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl]-3,5-b-
is-trifluoromethyl-benzamidine (3)
[0144] To a stirred solution of intermediate E (1.00 g) in dry
toluene (40 ml) and dry methylene chloride (6 ml), kept under
nitrogen, phosphorus pentachloride (1.9 g, 5 eq) is added and the
mixture refluxed for 20 hours. The reaction mixture is then
evaporated to dryness and the oil residue is taken up in dry
tetrahydrofuran (15 ml) and cannulated dropwise in a stirred
solution of an excess of hydroxylamine in absolute ethanol (50 ml),
under nitrogen and at O.degree. C. This latter is prepared mixing
sodium methoxide (0.99 g) and hydroxylamine hydrochloride (1.27 g)
in hot absolute ethanol and by filtering off the inorganic material
precipitated. The reaction mixture is stirred at room temperature
for 20 hours and then evaporated to dryness. The resulting solid
residue is purified by prep-LCMS, to afford the title compound as
yellowish solid (0.48 g yield.about.47%). LC-ESI-HRMS of [M-H]-
shows 559.0917 Da. Calc. 559.092886 Da, dev. -2.1 ppm.
Example 2
Biological Activity
Electrophysiological Determination
[0145] In this experiment we investigated the influence of the
compounds of the invention on the membrane currents when determined
electrophysiologically on Xenopus Oocytes capable of expressing
human BK channels, and the current through the channels is recorded
using the classical two-electrode voltage clamp technique.
[0146] The results of these determinations are presented in Table 1
below, and presented as the increase of BK current relative to the
basal current.
TABLE-US-00001 TABLE 1 Influence on BK Current Relative Increase of
Compound Concentration BK Current 1 30 .mu.M 1118% 2 30 .mu.M 252%
3 30 .mu.M 1342%
* * * * *